{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T09:09:40Z","timestamp":1790500180705,"version":"4.1.0"},"reference-count":59,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2019,11,2]],"date-time":"2019-11-02T00:00:00Z","timestamp":1572652800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"New York Blood Center","award":["NYB616 and NYB540"],"award-info":[{"award-number":["NYB616 and NYB540"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Zika virus (ZIKV) infection during pregnancy leads to severe congenital Zika syndrome, which includes microcephaly and other neurological malformations. No therapeutic agents have, so far, been approved for the treatment of ZIKV infection in humans; as such, there is a need for a continuous effort to develop effective and safe antiviral drugs to treat ZIKV-caused diseases. After screening a natural product library, we have herein identified four natural products with anti-ZIKV activity in Vero E6 cells, including gossypol, curcumin, digitonin, and conessine. Except for curcumin, the other three natural products have not been reported before to have anti-ZIKV activity. Among them, gossypol exhibited the strongest inhibitory activity against almost all 10 ZIKV strains tested, including six recent epidemic human strains. The mechanistic study indicated that gossypol could neutralize ZIKV infection by targeting the envelope protein domain III (EDIII) of ZIKV. In contrast, the other natural products inhibited ZIKV infection by targeting the host cell or cell-associated entry and replication stages of ZIKV. A combination of gossypol with any of the three natural products identified in this study, as well as with bortezomib, a previously reported anti-ZIKV compound, exhibited significant combinatorial inhibitory effects against three ZIKV human strains tested. Importantly, gossypol also demonstrated marked potency against all four serotypes of dengue virus (DENV) human strains in vitro. Taken together, this study indicates the potential for further development of these natural products, particularly gossypol, as the lead compound or broad-spectrum inhibitors against ZIKV and other flaviviruses, such as DENV.<\/jats:p>","DOI":"10.3390\/v11111019","type":"journal-article","created":{"date-parts":[[2019,11,4]],"date-time":"2019-11-04T04:13:08Z","timestamp":1572840788000},"page":"1019","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["Identification of Novel Natural Products as Effective and Broad-Spectrum Anti-Zika Virus Inhibitors"],"prefix":"10.3390","volume":"11","author":[{"given":"Yaning","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China"},{"name":"Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9864-8993","authenticated-orcid":false,"given":"Wanbo","family":"Tai","sequence":"additional","affiliation":[{"name":"Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning","family":"Wang","sequence":"additional","affiliation":[{"name":"Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shibo","family":"Jiang","sequence":"additional","affiliation":[{"name":"Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA"},{"name":"Key Laboratory of Medical Molecular Virology (MOE\/NHC\/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2761-0506","authenticated-orcid":false,"given":"Asim K.","family":"Debnath","sequence":"additional","affiliation":[{"name":"Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lanying","family":"Du","sequence":"additional","affiliation":[{"name":"Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizhong","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Natural Medicines, School of Pharmaceutical Sciences, Peking University, Beijing 100191, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4864","DOI":"10.1128\/JVI.00252-16","article-title":"Zika virus: New clinical syndromes and its emergence in the Western Hemisphere","volume":"90","author":"Lazear","year":"2016","journal-title":"J. Virol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/0035-9203(52)90042-4","article-title":"Zika virus (I). Isolations and serological specificity","volume":"46","author":"Dick","year":"1952","journal-title":"Trans. R. Soc. Trop. Med. Hyg."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S891","DOI":"10.1093\/infdis\/jix448","article-title":"Zika virus infection in pregnancy: Maternal, fetal, and neonatal considerations","volume":"216","author":"Zorrilla","year":"2017","journal-title":"J. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"6177","DOI":"10.1073\/pnas.1718476115","article-title":"Implications of Zika virus and congenital Zika syndrome for the number of live births in Brazil","volume":"115","author":"Castro","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1368","DOI":"10.1001\/jama.2017.1553","article-title":"Congenital Zika syndrome in 2017","volume":"317","author":"Lucey","year":"2017","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2142","DOI":"10.1056\/NEJMoa1601824","article-title":"Zika virus infection with prolonged maternal viremia and fetal brain abnormalities","volume":"374","author":"Driggers","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2321","DOI":"10.1056\/NEJMoa1602412","article-title":"Zika virus infection in pregnant women in Rio de Janeiro","volume":"375","author":"Brasil","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"687","DOI":"10.1007\/s00705-006-0903-z","article-title":"Full-length sequencing and genomic characterization of Bagaza, Kedougou, and Zika viruses","volume":"152","author":"Kuno","year":"2007","journal-title":"Arch. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.meegid.2019.01.018","article-title":"ZIKA virus entry mechanisms in human cells","volume":"69","author":"Agrelli","year":"2019","journal-title":"Infect. Genet. Evol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1007\/s13311-017-0575-2","article-title":"Therapeutic approaches for Zika virus infection of the nervous system","volume":"14","author":"Abrams","year":"2017","journal-title":"Neurotherapeutics"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1021\/acsinfecdis.8b00127","article-title":"Discovery of immunologically inspired small molecules that target the viral envelope protein","volume":"4","author":"Lian","year":"2018","journal-title":"ACS Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1016\/j.chembiol.2018.05.011","article-title":"Inhibition of flaviviruses by targeting a conserved pocket on the viral envelope protein","volume":"25","author":"Lian","year":"2018","journal-title":"Cell Chem. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.coi.2017.07.001","article-title":"The immunopathology of dengue and Zika virus infections","volume":"48","author":"Culshaw","year":"2017","journal-title":"Curr. Opin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"S7","DOI":"10.1038\/nrmicro2460","article-title":"Dengue: A continuing global threat","volume":"8","author":"Guzman","year":"2010","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1038\/s41426-017-0007-8","article-title":"Critical neutralizing fragment of Zika virus EDIII elicits cross-neutralization and protection against divergent Zika viruses","volume":"7","author":"Tai","year":"2018","journal-title":"Emerg. Microbes Infect."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/j.chom.2016.07.004","article-title":"A screen of FDA-approved drugs for inhibitors of Zika virus infection","volume":"20","author":"Barrows","year":"2016","journal-title":"Cell Host Microbe"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"e02187-18","DOI":"10.1128\/JVI.02187-18","article-title":"Rational design of Zika virus subunit vaccine with enhanced efficacy","volume":"93","author":"Tai","year":"2019","journal-title":"J. Virol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"29","DOI":"10.3389\/fmicb.2019.00029","article-title":"Transfusion-transmitted Zika virus infection in pregnant mice leads to broad tissue tropism with severe placental damage and fetal demise","volume":"10","author":"Tai","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4349","DOI":"10.1128\/AAC.48.11.4349-4359.2004","article-title":"N-substituted pyrrole derivatives as novel human immunodeficiency virus type 1 entry inhibitors that interfere with the gp41 six-helix bundle formation and block virus fusion","volume":"48","author":"Jiang","year":"2004","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1124\/pr.58.3.10","article-title":"Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies","volume":"58","author":"Chou","year":"2006","journal-title":"Pharmacol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"eaau8408","DOI":"10.1126\/sciadv.aau8408","article-title":"Triterpenoids manipulate a broad range of virus-host fusion via wrapping the HR2 domain prevalent in viral envelopes","volume":"4","author":"Si","year":"2018","journal-title":"Sci. Adv."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"15931","DOI":"10.1038\/s41598-017-16130-w","article-title":"Broad-spectrum antiviral agents: Secreted phospholipase A2 targets viral envelope lipid bilayers derived from the endoplasmic reticulum membrane","volume":"7","author":"Chen","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3106","DOI":"10.1128\/JVI.01456-10","article-title":"Identification of a small-molecule entry inhibitor for filoviruses","volume":"85","author":"Basu","year":"2011","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"10058","DOI":"10.1021\/jm5014067","article-title":"Discovery of pentacyclic triterpenoids as potential entry inhibitors of influenza viruses","volume":"57","author":"Yu","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1186\/1742-4690-9-104","article-title":"A bivalent recombinant protein inactivates HIV-1 by targeting the gp41 prehairpin fusion intermediate induced by CD4 D1D2 domains","volume":"9","author":"Lu","year":"2012","journal-title":"Retrovirology"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"15672","DOI":"10.1038\/ncomms15672","article-title":"A peptide-based viral inactivator inhibits Zika virus infection in pregnant mice and fetuses","volume":"8","author":"Yu","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_27","first-page":"e2830","article-title":"Time-of-addition and temperature-shift assays to determine particular step(s) in the viral life cycle that is blocked by antiviral substance(s)","volume":"8","author":"Chen","year":"2018","journal-title":"Bio-Protocol"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1046","DOI":"10.1038\/cr.2017.88","article-title":"Existing drugs as broad-spectrum and potent inhibitors for Zika virus by targeting NS2B-NS3 interaction","volume":"27","author":"Li","year":"2017","journal-title":"Cell Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"446","DOI":"10.1016\/j.immuni.2017.02.012","article-title":"25-Hydroxycholesterol protects host against Zika virus infection and its associated microcephaly in a mouse model","volume":"46","author":"Li","year":"2017","journal-title":"Immunity"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"ofw175","DOI":"10.1093\/ofid\/ofw175","article-title":"Adenosine analog NITD008 is a potent inhibitor of Zika virus","volume":"3","author":"Deng","year":"2016","journal-title":"Open Forum. Infect. Dis."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"13473","DOI":"10.1038\/ncomms13473","article-title":"Introduction of neutralizing immunogenicity index to the rational design of MERS coronavirus subunit vaccines","volume":"7","author":"Du","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"He, L., Tai, W., Li, J., Chen, Y., Gao, Y., Li, J., Sun, S., Zhou, Y., Du, L., and Zhao, G. (2019). Enhanced ability of oligomeric nanobodies targeting MERS coronavirus receptor-binding domain. Viruses, 11.","DOI":"10.3390\/v11020166"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1126\/science.aaf8505","article-title":"Specificity, cross-reactivity, and function of antibodies elicited by Zika virus infection","volume":"353","author":"Stettler","year":"2016","journal-title":"Science"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e00837-18","DOI":"10.1128\/JVI.00837-18","article-title":"A novel nanobody targeting Middle East respiratory syndrome coronavirus (MERS-CoV) receptor-binding domain has potent cross-neutralizing activity and protective efficacy against MERS-CoV","volume":"92","author":"Zhao","year":"2018","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.jinf.2017.03.006","article-title":"Anti-HIV antibody and drug combinations exhibit synergistic activity against drug-resistant HIV-1 strains","volume":"75","author":"Qi","year":"2017","journal-title":"J. Infect."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Wang, C., Hua, C., Xia, S., Li, W., Lu, L., and Jiang, S. (2019). Combining a fusion inhibitory peptide targeting the MERS-CoV S2 protein HR1 domain and a neutralizing antibody specific for the S1 protein receptor-binding domain (RBD) showed potent synergism against pseudotyped MERS-CoV with or without mutations in RBD. Viruses, 11.","DOI":"10.3390\/v11010031"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.antiviral.2017.03.014","article-title":"Curcumin inhibits Zika and chikungunya virus infection by inhibiting cell binding","volume":"142","author":"Mounce","year":"2017","journal-title":"Antivir. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1007\/s00705-013-1849-6","article-title":"Inhibitory effects of curcumin on dengue virus type 2-infected cells in vitro","volume":"159","author":"Padilla","year":"2014","journal-title":"Arch. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1943","DOI":"10.1038\/s41467-019-09914-3","article-title":"Differential human antibody repertoires following Zika infection and the implications for serodiagnostics and disease outcome","volume":"10","author":"Ravichandran","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.cell.2016.07.020","article-title":"Structural basis of Zika virus-specific antibody protection","volume":"166","author":"Zhao","year":"2016","journal-title":"Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1016\/j.cell.2017.04.024","article-title":"Recurrent potent human neutralizing antibodies to Zika virus in Brazil and Mexico","volume":"169","author":"Robbiani","year":"2017","journal-title":"Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2125","DOI":"10.1016\/S0140-6736(16)00651-6","article-title":"Association between Zika virus and microcephaly in French Polynesia, 2013\u20132015: A retrospective study","volume":"387","author":"Cauchemez","year":"2016","journal-title":"Lancet"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/S0140-6736(17)31368-5","article-title":"Infection-related microcephaly after the 2015 and 2016 Zika virus outbreaks in Brazil: A surveillance-based analysis","volume":"390","author":"Carmo","year":"2017","journal-title":"Lancet"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Krauer, F., Riesen, M., Reveiz, L., Oladapo, O.T., Martinez-Vega, R., Porgo, T.V., Haefliger, A., Broutet, N.J., Low, N., and WHO Zika Causality Working Group (2017). Zika virus infection as a cause of congenital brain abnormalities and Guillain\u2013Barr\u00e9 syndrome: Systematic review. PLoS Med., 14.","DOI":"10.1371\/journal.pmed.1002203"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"272","DOI":"10.1016\/j.jns.2017.09.001","article-title":"Zika virus disease-associated Guillain-Barr\u00e9 syndrome\u2014Barranquilla, Colombia 2015\u20132016","volume":"381","author":"Salinas","year":"2017","journal-title":"J. Neurol. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1002\/jps.2600640654","article-title":"Letter: Antiviral activity of gossypol and apogossypol","volume":"64","author":"Dorsett","year":"1975","journal-title":"J. Pharm. Sci."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2427","DOI":"10.1021\/jm00013a018","article-title":"Synthesis and anti-HIV activity of 1,1\u2032-dideoxygossypol and related compounds","volume":"38","author":"Royer","year":"1995","journal-title":"J. Med. Chem."},{"key":"ref_48","first-page":"615","article-title":"Study of antiviral effect of gossypol on chick embryo model","volume":"32","author":"Goriunova","year":"1969","journal-title":"Farmakol. Toksikol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"2149","DOI":"10.1128\/AAC.33.12.2149","article-title":"Selective inhibition of human immunodeficiency virus type 1 replication by the (-) but not the (+) enantiomer of gossypol","volume":"33","author":"Lin","year":"1989","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1517\/13543784.14.11.1419","article-title":"Investigations on gossypol: Past and present developments","volume":"14","author":"Dodou","year":"2005","journal-title":"Expert Opin. Investig. Drugs"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.2174\/0929867033456369","article-title":"Mechanism of drug and toxic actions of gossypol: Focus on reactive oxygen species and electron transfer","volume":"10","author":"Kovacic","year":"2003","journal-title":"Curr. Med. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.tox.2012.09.010","article-title":"Gossypol-induced suicidal erythrocyte death","volume":"302","author":"Zbidah","year":"2012","journal-title":"Toxicology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"C166","DOI":"10.1152\/ajpcell.1994.267.1.C166","article-title":"Permeabilization of MDCK cells with cholesterol binding agents: Dependence on substratum and confluency","volume":"267","author":"Zurzolo","year":"1994","journal-title":"Am. J. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/0005-2736(95)00253-7","article-title":"Glycoalkaloids selectively permeabilize cholesterol containing biomembranes","volume":"1279","author":"Keukens","year":"1996","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1042\/bj3050529","article-title":"Streptolysin-O induces release of glycosylphosphatidylinositol-anchored alkaline phosphatase from ROS cells by vesiculation independently of phospholipase action","volume":"305","author":"Xie","year":"1995","journal-title":"Biochem. J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/0009-3084(95)02455-R","article-title":"Differential solubilization of lipids along with membrane proteins by different classes of detergents","volume":"77","author":"Banerjee","year":"1995","journal-title":"Chem. Phys. Lipids"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1091\/mbc.8.3.533","article-title":"Specific release of membrane-bound annexin II and cortical cytoskeletal elements by sequestration of membrane cholesterol","volume":"8","author":"Harder","year":"1997","journal-title":"Mol. Biol. Cell"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1186\/1475-2875-12-194","article-title":"Anti-malarial property of steroidal alkaloid conessine isolated from the bark of Holarrhena antidysenterica","volume":"12","author":"Dua","year":"2013","journal-title":"Malar. J."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3390\/ph8010001","article-title":"Clinical use of proteasome inhibitors in the treatment of multiple myeloma","volume":"8","author":"Merin","year":"2015","journal-title":"Pharmaceuticals"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/11\/11\/1019\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:31:28Z","timestamp":1760189488000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/11\/11\/1019"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,2]]},"references-count":59,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2019,11]]}},"alternative-id":["v11111019"],"URL":"https:\/\/doi.org\/10.3390\/v11111019","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,2]]}}}